Anticancer and antimicrobial drugs do not target the organ of interest when given orally. For example, in lung cancer and various pulmonary infections, it has not been possible to target oral drugs to the site of disease. For example, cidofovir has been identified as an active antiviral against vaccinia and smallpox (De Clercq, Clinical Microbiology Reviews, 14:382-397, 2001 and Baker et al., Antiviral Res. 57: 13-23, 2003.) but it is not orally active (Cundy K. C., Clinical Pharmacokinetics, 36:127-143, 1999). However, alkoxyalkyl esters of cidofovir (CDV) were orally active and several orders of magnitude more active than CDV in vitro against vaccinia, cowpox, ectromelia, variola and monkeypox (Kern, E. R., et al., Antimicrobial Agents Chemotherapy, 46:991-995, 2002; Buller, R. M, et al., Virology, 318:474-481, 2004 and Huggins, J. W., et al., Antiviral Research, 53:A66 (104), 2002). Two of these compounds, hexadecyloxypropyl-CDV (HDP-CDV) and octadecyloxyethyl-CDV (ODE-CDV), are highly protective in various orthopoxvirus lethal challenge models in mice but do not lower viral titers in the lung (Buller, R. M, et al., Virology, 318:474-481, 2004 and Quenelle, D. C., et al., Antimicrobial Agents Chemotherapy, 48:404-412, 2004). Alkoxyalkyl cidofovir analogs are only weakly active in lowering lung viral titers in ectromelia virus infected mice from 3×106 to 105 pfu/gm (Buller, R. M, et al., Virology, 318:474-481, 2004) or not active at all in lowering lung viral titers in cowpox- or vaccinia virus-infected mice (Quenelle, D. C., et al., Antimicrobial Agents Chemotherapy, 48:404-412, 2004). The effect of oral treatment with CDV, HDP-CDV and ODE-CDV on mortality from a lethal aerosol challenge with ectromelia virus has been examined. Four hours after infection, drugs were administered orally for 5 days. Mortality is noted at 21 days. At 7 days a subset of animals was sacrificed and tissues obtained for assessment of viral titers/gm tissue.
LiverDrugMg/kgMortalitytiterSpleen titerLung titerOral CDV10 × 5 d100%3 × 1063 × 1063 × 106HDP-CDV10 × 5 d0%<102<1025 × 104ODE-CDV 5 × 5 d0%<102<1023 × 105Ectromelia infection, 2.3 × 104 pfu by small particle aerosol, A/NCR mice;titers pfu/mL (Adapter from Buller, et al. (2004) Virology, 318, 474-481).
This study clearly shows the problem. While both alkoxyalkyl esters, HDP-CDV and ODE-CDV, prevent death from a lethal challenge with ectromelia virus, neither reduced lung viral titers greatly even though viral titers in liver and spleen were below the limit of detection. Similar results were noted in cowpox and vaccinia virus challenge experiments by Quenelle et al. Current alkoxyalkyl conjugates of nucleoside phosphonates and acyclic nucleoside phosphonates do not deliver substantial amounts of drug to lung.
Oral drugs are usually taken up from the small intestine into the portal vein which exposes the drug to the liver and liver first pass drug metabolism which may be very rapid. Very small amounts of the drug administered reach the lung where the infection or lung cancer resides. Therefore, there is a need to develop compounds that target oral antiviral, antifungal, antibacterial or anticancer compounds to the lung.